A presentation by Dr Janet Allen from the Cystic Fibrosis Trust regarding the impact of genome technologies in Cystic Fibrosis research, delivered at Sano Genetics' Demystifying Genomics for Patient Registries Event on 11th July 2019.

1. Cystic Fibrosis
Impact of genome technologies
July 11, 2019
Dr Janet Allen, Director of Strategic Innovation
1

2. Clinical characteristics
▪ Classic Mendelian genetics: autosomal recessive
▪ 1:25 people in UK are asymptomatic carriers
▪ 1:2000 Live births
▪ Complex condition – sticky mucus
▪ Lungs:
▪ Chronic decline in lung function following repeated infections
▪ Multidrug resistant infections
▪ Unusual infections
▪ Gut: malabsorption
▪ Pancreas: failed endocrine and exocrine pancreas
1938. Dorothy
Andersen first
describes ‘fibrocystic
disease of the
pancreas’

3. 1989 Gene identified CFTR
▪ 1989. Gene responsible for CF
identified
▪ Herculian effort led by Lap-Chee
Tsui, Francis Collins and Jack Riordan
▪ Chromosome 7
▪ Gene 189kb
▪ 26 introns + 27 exons
▪ 1,480 amino acids
▪ 5 protein domains

4. Impact of CFTR identification
1989
Antenatal diagnosis (PGD)
2007: New Born Screening
2001: Gene therapies,
on going
2005–2012: Precision
Medicine. Small molecule
disease modifiers

5. CF: Factors that make
a success story
Mediansurvivalage
0
10
20
30
40
Calendar year
1930 1940 1950 1960 1970 1980 1990 2000 2010
Antibiotics.
Airway
Clearance.
Nutrition.
Delivery
DNase
Transplant
Development of
transformational
therapies
2020
Cystic Fibrosis Centres
Ivacafto
r

6. CF-causing mutations
▪ Mendelian genetics – need
mutation on both CFTR genes
▪ Over 2,000 mutations in CFTR
identified
▪ Of these, ~600 are CF-causing
mutations
▪ CFTR2 = International data site
managed at John Hopkins
▪ All varieties: Missense,
nonsense, codon deletions,
splice sites
Splice variants
Stop codons (X)
Misfolding
F508del
Gating mutations
e.g. G551D

7. CFTR: Apical membrane anion channel
▪ I = NγPo
Current
N = Number of channels
at the cell surface
• F508Del
• Nonsense mutations
• Splice variants
Po = Open probability of the channel
• G551D
• R117H

8. CFTR: Precision medicines
▪ I = NγPo
Current
N = Number of channels
at the cell surface
• F508Del
• Nonsense mutations
• Splice variants
Po = Open probability of the channel
• G551D
• R117H

9. CFTR: Precision medicines
▪ I = NγPo
Current
N = Number of channels
at the cell surface
• F508Del
• Nonsense mutations
• Splice variants
Po = Open probability of the channel
• G551D
• R117H
POTENTIATORS
IVACAFTOR
TRIPLE COMBO
1. Read through
2. NMD inhibitors
Gene and cell based therapies. Gene and base editing

10. UK statistics
▪ 10,500 people with CF in UK
▪ CF Trust hosts the UK CF Registry ~99% of people
▪ Records genotype and annual phenotype ~90%
▪ Most frequent mutations:
▪ F508del. 90% of people have 1 copy. 40% are heterozygote
▪ G551D
▪ G542X
▪ W1282X
▪ R117H
▪ ?/??
▪ Mutations influence function of CFTR
In 2014, up to10% of registry entries

11. Why does the UK CF registry have
genotype gaps?
▪ Before 2007:
▪ Cystic fibrosis diagnosed clinically.
▪ Genotyping completed but usually only a limited subset
of common mutations.
▪ Treatments and clinical care: independent of genotype.
▪ 2007:
▪ Introduction of new born screening in UK
▪ Earlier diagnosis but clinical management remains
genotype independent
▪ 2012:
▪ Genotype specific therapies introduced
▪ Eligibility for drug (ivacaftor/Kalydeco) reimbursement
only for certain genotypes

12. UK experience.
2014: Gaps really begin to matter
▪ 2014
▪ EMA approval to extend indication for ivacaftor to non-G551D
gating mutations
▪ G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P,
G1349D, G970R
▪ Many of these mutations are rare and not on routine genotype
screening panels
▪ So those carrying these mutations may appear as ?/? or
?/known: so not able to benefit July 31, 2014
Vertex Receives European Approval for
KALYDECO™ (ivacaftor) in Eight
Non-G551D Gating Mutations
-In Europe, approximately 250 people
ages 6 and older have one of 8 additional
gating mutations-

13. Pilot study in 5 centres:
210 people with ?? Or ?/known
▪ Two people carrying G551D identified.
▪ Five people carrying non-G551D gating mutations:
▪ Four G178R
▪ One S549N
▪ All eligible to receive ivacaftor
▪ One newly identified mutation: L1135P
▪ Not previously reported in CFTR1 or CFTR2 datasets
▪ Most frequent codon change introduction of premature Stop (X)
Number of
patients
Attending
adult CF
Centres
Attending
paediatric
CF Centres
Mutation missing
on one allele
?/known
148 127 21
Mutation missing
on both alleles
?/?
62 54 8
Total
210 181 29

14. Why does this matter?
▪ Non G551D gating mutations.
▪ Rare but responsive to ivacaftor
▪ Many not on routine screen so need full
exon sequencing
▪ PTC/Stop/X codons.
▪ Most frequently identified mutation in this
cohort
▪ Approx 10% of 210
▪ Potential new therapies on the horizon
G542X
W1282X
R553X
First 3 represent 50% of Stop codons
Long tail of rare mutations

15. Fixing CFTR is not sufficient
▪ Gene modulaters outside CFTR
influence CF phenotype
▪ GWAS identified hotspots
▪ SLC26A9 – severe gut pathology
and diabetes
▪ Variation in response to drugs

16. cysticfibrosis.org.uk
Thank you